19-40608363-T-C

Variant names:

• chr19-40608363-T-C
• rs34545902
• NM_001042545.2:c.1300T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001042545.2(LTBP4):​c.1300T>C​(p.Ser434Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S434T) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LTBP4 NM_001042545.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.25
• Publications: 5 publications found

Genes affected

LTBP4 (HGNC:6717): (latent transforming growth factor beta binding protein 4) The protein encoded by this gene binds transforming growth factor beta (TGFB) as it is secreted and targeted to the extracellular matrix. TGFB is biologically latent after secretion and insertion into the extracellular matrix, and sheds TGFB and other proteins upon activation. Defects in this gene may be a cause of cutis laxa and severe pulmonary, gastrointestinal, and urinary abnormalities. Three transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, May 2010]

LTBP4 Gene-Disease associations (from GenCC):

• cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.030589074).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LTBP4	NM_001042545.2	c.1300T>C	p.Ser434Pro	missense_variant	Exon 8 of 30	ENST00000396819.8	NP_001036010.1
LTBP4	NM_001042544.1	c.1501T>C	p.Ser501Pro	missense_variant	Exon 11 of 33		NP_001036009.1
LTBP4	NM_003573.2	c.1390T>C	p.Ser464Pro	missense_variant	Exon 11 of 33		NP_003564.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LTBP4	ENST00000396819.8	c.1300T>C	p.Ser434Pro	missense_variant	Exon 8 of 30	1	NM_001042545.2	ENSP00000380031.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	13
DANN	Benign	0.96
DEOGEN2	Benign	0.038	T;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.0095	N
LIST_S2	Benign	0.58	T;T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.031	T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-1.8	.;N;.
PhyloP100		1.2
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.51	N;N;N
REVEL	Benign	0.11
Sift	Benign	0.35	T;T;T
Sift4G	Benign	0.30	T;T;T
Polyphen		0.0	.;B;.
Vest4		0.18
MutPred		0.30		.;Loss of phosphorylation at S501 (P = 0.0088);.;
MVP		0.10
MPC		0.43
ClinPred		0.058	T
GERP RS		2.0
Varity_R		0.080
gMVP		0.38
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs34545902; hg19: chr19-41114269;